RESUMEN
Infant leukemia (IL) is a rare sporadic cancer with a grim prognosis. Although most cases are accompanied by MLL rearrangements and harbor very few somatic mutations, less is known about the genetics of the cases without MLL translocations. We performed the largest exome-sequencing study to date on matched non-cancer DNA from pairs of mothers and IL patients to characterize congenital variation that may contribute to early leukemogenesis. Using the COSMIC database to define acute leukemia-associated candidate genes, we find a significant enrichment of rare, potentially functional congenital variation in IL patients compared with randomly selected genes within the same patients and unaffected pediatric controls. IL acute myeloid leukemia (AML) patients had more overall variation than IL acute lymphocytic leukemia (ALL) patients, but less of that variation was inherited from mothers. Of our candidate genes, we found that MLL3 was a compound heterozygote in every infant who developed AML and 50% of infants who developed ALL. These data suggest a model by which known genetic mechanisms for leukemogenesis could be disrupted without an abundance of somatic mutation or chromosomal rearrangements. This model would be consistent with existing models for the establishment of leukemia clones in utero and the high rate of IL concordance in monozygotic twins.
Asunto(s)
Biomarcadores de Tumor/genética , Reordenamiento Génico , Leucemia Mieloide Aguda/genética , Mutación/genética , Proteína de la Leucemia Mieloide-Linfoide/genética , Polimorfismo de Nucleótido Simple/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adulto , Estudios de Casos y Controles , Niño , Femenino , N-Metiltransferasa de Histona-Lisina , Humanos , Lactante , Leucemia Mieloide Aguda/congénito , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/congénito , Pronóstico , Tasa de Supervivencia , Adulto JovenRESUMEN
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Excessive early childhood adiposity is a prevalent and increasing concern in many parts of the world. Parental obesity is one of the several factors previously associated with infant and early childhood weight, length and adiposity. Parental obesity represents a surrogate marker of the complex interplay among genetic, epigenetic and shared environmental factors, and is potentially modifiable. The relative contributions of maternal and paternal body mass index (BMI) to infant and early childhood growth, as well as the timing of such effects, have not been firmly established. WHAT THIS STUDY ADDS: Utilizing serial infant measurements and growth curve modelling, this is the largest study to fully characterize and formally compare associations between maternal and paternal BMI and offspring growth across the entire infancy and early childhood period. Maternal obesity is a stronger determinant of offspring BMI than paternal obesity at birth and from 2 to 3 years of age, suggesting that prevention efforts focused particularly on maternal lifestyle and BMI may be important in reducing excess infant BMI. The observation that maternal BMI effects are not constant, but rather present at birth, wane and re-emerge during late infancy, suggests that there is a window of opportunity in early infancy when targeted interventions on children of obese mothers may be most effective. BACKGROUND/OBJECTIVE: Parental obesity influences infant body size. To fully characterize their relative effects on infant adiposity, associations between maternal and paternal body mass index (BMI) category (normal: ≤25 kg m(-2) , overweight: 25 - <30 kg m(-2) , obese: ≥30 kg m(-2) ) and infant BMI were compared in Fels Longitudinal Study participants. METHODS: A median of 9 serial weight and length measures from birth to 3.5 years were obtained from 912 European American children born in 1928-2008. Using multivariable mixed effects regression, contributions of maternal vs. paternal BMI status to infant BMI growth curves were evaluated. Cubic spline models also included parental covariates, infant sex, age and birth variables, and interactions with child's age. RESULTS: Infant BMI curves were significantly different across the three maternal BMI categories (Poverall < 0.0001), and offspring of obese mothers had greater mean BMI at birth and between 1.5 and 3.5 years than those of over- and normal weight mothers (P ≤ 0.02). Average differences between offspring of obese and normal weight mothers were similar at birth (0.8 kg m(-2) , P = 0.0009) and between 2 and 3.5 years (0.7-0.8 kg m(-2) , P < 0.0001). Infants of obese fathers also had BMI growth curves distinct from those of normal weight fathers (P = 0.02). Infant BMI was more strongly associated with maternal than paternal obesity overall (P < 0.0001); significant differences were observed at birth (1.11 kg m(-2) , P = 0.006) and from 2 to 3 years (0.62 kg m(-2) , P3 years = 0.02). CONCLUSION: At birth and in later infancy, maternal BMI has a stronger influence on BMI growth than paternal BMI, suggesting weight control in reproductive age women may be of particular benefit for preventing excess infant BMI.
Asunto(s)
Hijo de Padres Discapacitados , Padre , Madres , Obesidad , Adiposidad/genética , Adulto , Índice de Masa Corporal , Hijo de Padres Discapacitados/estadística & datos numéricos , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Estudios Longitudinales , Masculino , Obesidad/epidemiología , Obesidad/genética , Prevalencia , Encuestas y Cuestionarios , Factores de Tiempo , Estados Unidos/epidemiología , Población BlancaRESUMEN
BACKGROUND: Prenatal supplementation has been inversely associated with childhood, but not with infant, leukaemia. METHODS: Mothers of 443 cases of infant leukaemia diagnosed during 1996-2006 and 324 frequency-matched controls completed interviews. Associations were evaluated by unconditional logistic regression. RESULTS: We observed no associations between prenatal vitamin (odds ratio (OR)=0.79, 95% confidence interval (CI): 0.44-1.42) or iron supplementation (OR=1.07, 95% CI: 0.75-1.52) and infant leukaemia after adjustment for race/ethnicity and income. Similar results were observed for leukaemia subtypes analysed separately. CONCLUSION: The observed null associations may be attributable to high supplementation rates and/or national fortification programmes.
Asunto(s)
Hierro de la Dieta/administración & dosificación , Leucemia/etiología , Vitaminas/administración & dosificación , Adulto , Suplementos Dietéticos , Femenino , Humanos , Modelos Logísticos , Masculino , Embarazo , RiesgoRESUMEN
METHODS: Maternally reported congenital abnormalities (CAs) were examined in a case-control study of 278 cases of paediatric germ cell tumours (GCTs) and 423 controls. RESULTS AND CONCLUSIONS: Germ cell tumours were significantly associated with cryptorchidism in males (OR=10.8, 95% CI: 2.1-55.1), but not with any other specific CA in either sex.